AKT1 E17K Inhibits Cancer Cell Migration by Abrogating β-Catenin Signaling

Area of Science:

• Molecular Oncology
• Cancer Genetics
• Cell Signaling

Background:

• The PI3K/AKT pathway is frequently activated in cancer, but PI3K and AKT inhibitors have shown limited clinical success.
• Understanding the specific roles of AKT isoforms in cancer progression is crucial for developing effective targeted therapies.

Purpose of the Study:

• To investigate the biological impact of the AKT1 E17K mutation using a CRISPR-edited isogenic system.
• To elucidate the molecular mechanisms underlying the effects of AKT1 activation on cancer cell migration and invasion.

Main Methods:

• CRISPR-mediated gene editing to create an AKT1 E17K-mutant isogenic system in a TP53-null background.
• Analysis of cell growth, colony formation, migration, and invasion.
• Investigation of E-cadherin, ZEB1, and β-catenin expression and localization.

Main Results:

• AKT1 E17K expression enhanced cell growth and colony formation but paradoxically inhibited cell migration and invasion.
• This inhibition was mediated by increased E-cadherin expression due to suppressed ZEB1 transcription via altered β-catenin localization.
• AKT2 activation had opposing effects, reducing E-cadherin expression, and AKT1's pro-migratory effect was absent in cells with PTEN loss or PIK3CA mutations.

Conclusions:

• The AKT1 E17K mutation impairs breast cancer cell migration/invasiveness through a mechanism involving increased E-cadherin and decreased ZEB1, reversing epithelial-mesenchymal transition.
• Targeting AKT inhibitors in breast cancer patients with specific genetic alterations (e.g., AKT1 mutation) could potentially accelerate metastatic progression.
• Frequent co-selection for CDH1 mutations in AKT1-mutated breast tumors may be explained by this AKT1-specific inhibitory effect on migration.